ABSTRACT Patients with chronic heart failure (HF) are characterized by disability and exercise intolerance which impair their quality of life and depict a major source of morbidity in this population. A cardinal determinant of these characteristics is the occurrence of premature fatigue during physical activity. Based on earlier studies in healthy young humans, neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents, well-known to be abnormally elevated in patients with HF, might play a key role in these abnormalities. However, even in healthy older humans, our understanding of the exact role / relative contribution of group III/IV muscle afferents to the development of fatigue during exercise is incomplete. By studying patients with HF with preserved (HFPEF) as well as reduced (HFREF) ejection fraction and age- and activity-matched healthy controls (CTRLs), we will evaluate the impact of heart failure on a) the precise development of central and peripheral fatigue during exercise, and b) the relative contribution of group III/IV muscle afferents to exercise tolerance and fatigue resistance during physical activity in humans. Specifically, we will compare the development of central and peripheral fatigue during whole body (i.e. bicycle) as well as single muscle (i.e. single leg knee-extension) exercise in HFPEF, HFREF, and CTRLs (using electric femoral nerve stimulation, electric cervicomedullary stimulation, and transcranial magnetic stimulation techniques). Furthermore, we will use lumbar intrathecal fentanyl to temporarily block the central projection of group III/IV muscle afferents during exercise (lumbar intrathecal has no concomitant effect on feedforward drive at a given absolute workload). This unique and previously proven approach to temporarily block group III/IV muscle afferent feedback will enable us to evaluate the effects of these sensory neurons on the development of central and peripheral fatigue during large and small muscle mass rhythmic exercise in CTRLS and in patients with HF. The knowledge gained from this research in humans with different types of HF will contribute to a better understanding of the role of muscle afferent feedback as a potential mechanism underlying the premature fatigue characterizing this population. Additionally, if we can confirm preliminary findings demonstrating that blocking the abnormal feedback from the muscles in HF reduces the debilitating effects of fatigue in this population, then we could provide a theoretical foundation for the design of new and innovative pharmaceutical and especially rehabilitative treatment strategies. For example, the innovation of a specific therapy that down-regulates the feedback from these sensory nerves to the brain and spinal cord, may effectively improve the patients' success in cardiac rehabilitation and consequently quality of life and mortality.